Exploring the Role of Testosterone as a Novel Anti-Nociceptive Agent in Women with Chronic Pain and Opioid Use

项目摘要 有大量的证据表明，女性和男性并不平等地经历疼痛。与男性相比，女性 在大多数临床疼痛病症中过度表现，并且还表现出对 实验性疼痛同样，女性使用止痛药的比例是男性的两倍， 严重程度相当女性的血清睾酮浓度不仅比男性低20倍， 男性也会随着年龄的增长而减少睾丸激素水平。综合来看，这些数据表明， 睾酮具有抗伤害性，这可以解释为什么女性有更高的发病率， 与男性相比，慢性疼痛的严重程度。此外，接受阿片类镇痛药治疗的患者 由于阿片类药物有效地抑制性腺轴，慢性疼痛经历睾丸激素水平的进一步降低。 绝经前和绝经后长期服用阿片类药物的女性睾酮水平下降>50% 与不使用阿片类药物的女性相比。近年来，持续作用阿片类药物在管理中的使用 慢性非癌症疼痛的发病率随着许多妇女服用多种阿片类镇痛药而增加。的发展 阿片样物质诱导的性腺功能减退剥夺了这些妇女的睾酮的抗伤害感受特性， 导致恶性循环，尽管服用阿片类药物，但慢性疼痛仍会持续，使患者 长期需要更高剂量的阿片类药物。以前的试验睾酮替代男性 阿片类药物诱导的性腺功能减退症在临床和实验性疼痛方面均显示出改善， 改善生活质量（QOL）。然而，尽管慢性疼痛的负担显著更高， 睾酮替代对疼痛感知和耐受性的功效尚未在女性中进行研究。 本提案的总体目标是评估生理性睾酮替代治疗在 改善绝经后妇女临床和实验性疼痛的双盲随机对照试验 患有慢性背痛的女性，正在接受阿片类镇痛药治疗至少6个月， 睾酮.我们还将评估睾酮替代治疗对生活质量、情绪和身体的影响。 功能我们建议进行一项为期12周的双盲、随机对照、概念验证试验，以确定 每周一次肌肉注射与安慰剂注射相比生理性睾酮替代的疗效 在患有慢性背痛和睾酮缺乏的60岁及以上女性中。以下结果 将测量：1）临床疼痛，2）定量感觉测试的实验性疼痛，3）QOL，情绪 和身体功能。因为慢性疼痛是一个主要的公共卫生问题，现有的治疗方法 次优，仅提供部分缓解，如果该试验证实睾酮治疗的益处，患者将 有一种便宜的、相对安全的、易于给药的药物， 改变对这些病人的护理。

PROJECT SUMMARY There is abundant evidence that women and men do not experience pain equally. Compared to men, women are overrepresented in the majority of clinical pain conditions and also exhibit greater sensitivity to experimental pain. Similarly, use of analgesics is twice as common in women, compared to men, for conditions of comparable severities. Women not only have 20-fold lower serum testosterone concentrations compared to men but also experience a reduction in testosterone levels with age. Taken together, these data suggest that testosterone has anti-nociceptive properties which may explain why women have a higher incidence and severity of chronic pain compared to men. Additionally, patients who are prescribed opioid-analgesics for chronic pain experience further reduction in testosterone levels as opioids potently suppress the gonadal axis. Both pre- and postmenopausal women on chronic opioids demonstrate >50% reduction in testosterone levels compared to women not using opioids. In recent years, the use of sustained-action opioids in the management of chronic non-cancer pain has grown with many women taking multiple opioid analgesics. The development of opioid-induced hypogonadism deprives these women of the anti-nociceptive properties of testosterone and leads to a vicious cycle resulting in perpetuation of chronic pain despite being on opioids, subjecting patients to long-term requirement of even higher doses of opiates. Previous trials of testosterone replacement in men with opioid-induced hypogonadism have shown improvement in both clinical and experimental pain, and improvement in quality of life (QOL). However, despite having significantly higher burden of chronic pain, the efficacy of testosterone replacement on pain perception and tolerance has not been studied in women. The overall goal of this proposal is to evaluate the efficacy of physiologic testosterone replacement in improving clinical and experimental pain in a double-blind, randomized-controlled trial in postmenopausal women with chronic back pain who are being treated with opioid-analgesics for at least 6 months and have low testosterone. We will also assess the efficacy of testosterone replacement on QOL, mood and physical function. We propose a 12-week double-blind, randomized-controlled, proof-of-concept trial to determine the efficacy of physiologic testosterone replacement with weekly intramuscular injections versus placebo injections in women age 60 years and older with chronic back pain and testosterone deficiency. The following outcomes will be measured: 1) clinical pain, 2) experimental pain with quantitative sensory testing, and 3) QOL, mood and physical function. Because chronic pain is a major public health problem for which existing therapies are suboptimal and only provide partial relief, if this trial confirms benefits of testosterone therapy, patients will have an inexpensive, relatively safe and easy to administer medication available that has the potential to transform the care of these patients.